Orodispersible pharmaceutical composition comprising ivabradine

ABSTRACT

The invention relates to a solid orodispersible pharmaceutical composition of ivabradine, characterised in that it comprises ivabradine or a pharmaceutically acceptable salt thereof and granules consisting of co-dried lactose and starch.

The present invention relates to a solid orodispersible pharmaceuticalform for the administration of ivabradine or a pharmaceuticallyacceptable salt thereof by the oral route, without the simultaneousdrinking of a glass of water and without the problem of swallowing.

Ivabradine, or3-(3-{[((7S)-3,4-dimethoxybicyclo[4,2,0]octa-1,3,5-trien-7-yl)methyl]-methylamino}propyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one,is an exclusively bradycardic, sino-atrial regulator for use in thetreatment of stable angina, heart failure and acute ischaemia.

The doses of ivabradine enabling the desired therapeutic effect to beobtained are generally of the order of from 1 mg to 20 mg, administeredin the form of an immediate-release tablet.

Many people have difficulty in swallowing conventional tablets, the sizeof which is often not negligible. The problems associated with theingestion of medicines (choking; suffocation as a result of obstructionof the throat) are often the cause of poor compliance with dosageregimens or, indeed, of discontinuation of treatment.

The pharmaceutical compositions of the present invention make itpossible not only to solve the known problems of a tablet form that hasto be swallowed but also to offer a superior medical service whichespecially allows the quality of life of patients to be improved.

The orodispersible pharmaceutical composition of ivabradine has theadvantage that elevated plasma levels of active ingredient are obtainedrapidly.

The orodispersible pharmaceutical composition according to the inventionhas the particular characteristic of requiring neither water nor chewingin the course of its administration. It disintegrates very rapidly inthe mouth, preferably in less than three minutes and even morepreferably in less than one minute.

Many rapid-dissolution forms are described in the prior art. In general,it is common to the previously described technologies that they use adisintegrating agent such as Kollidon® CL (crosslinkedpolyvinylpyrrolidone), EXPLOTAB® (carboxymethyl starch) and AC DISOL®(crosslinked sodium carboxymethylcellulose).

That disintegrating agent is indispensable to the formulation of theorodispersible tablets and has to be used in conjunction with adirect-compression excipient. The difficulties encountered in themanufacture of such tablets reside in the fact that it is very difficultto obtain tablets having physical characteristics that are constant andreproducible and compatible with the customary handling requirements oftablets.

However, the customarily used mixtures result in tablets of veryconsiderable hardness which is completely unsuitable for rapiddisintegration in the oral cavity.

Other orodispersible forms can be produced by using lyophilisation,resulting in very porous solid forms called “oral lyophilisates”. Thoseforms require the use of a highly specific and complicated industrialprocess which is lengthy to carry out, yielding a medicament form whichhas a high cost price.

The present invention enables those problems to be solved. It relates toa solid orodispersible form of ivabradine comprising a single excipientof natural origin which allows rapid disintegration and which has aneutral flavour and agreeable texture. The said excipient acts both asbinder and as disintegrant. It allows a simple ivabradine formulation tobe obtained, having excellent suitability for direct compression,resulting in tablets of low -friability and of a hardness that iscompatible with customary handling methods.

More specifically, the invention relates to a solid orodispersiblepharmaceutical composition of ivabradine or a pharmaceuticallyacceptable salt thereof, characterised in that it comprises:

-   -   ivabradine or a pharmaceutically acceptable salt thereof,    -   and granules consisting of co-dried lactose and starch.

The composition according to the invention may also comprise, forreasons of tablet manufacture, one or more lubricants and a flow agent,as well as flavourings, colourings and sweetening agents asconventionally used.

In the pharmaceutical compositions according to the invention, theivabradine is preferably in its hydrochloride form.

The invention relates also to the use of granules consisting of co-driedlactose and starch in the manufacture of solid orodispersiblepharmaceutical compositions of ivabradine.

The term “orodispersible” is understood to refer to solid pharmaceuticalcompositions which disintegrate in the oral cavity in less than 3minutes, preferably less than one minute.

The said granules present in the solid pharmaceutical compositionsaccording to the invention correspond to the compositions described inPatent Application EP 00/402159.8. Those granules are characterised by aspherical structure and an advantageous compressibility and are marketedunder the name STARLAC®.

The disintegrating properties of the said granules are known for tabletsplaced in large volumes of stirred liquids. It is especially surprisingthat, when used in the manufacture of orodispersible forms, the saidgranules should give especially satisfactory results in terms ofdisintegration in the mouth, for two reasons.

The first reason is based on the finding that the least water-solubleexcipients are the most suitable for the formulation of orodispersibletablets (dissolution, in bringing about an increase in the viscosity ofwater, slows down its penetration into the tablets) and yet the saidgranules contain a large amount of highly water-soluble lactose.Moreover, the starch contained in the said granules is not a“super-disintegrant” agent as used and described in the orodispersibleforms of the prior art. The second is based on the finding that thedisintegrant properties of an excipient (used in a tablet), whendetermined in water using conventional methods, cannot be extrapolatedto the behaviour of the same tablet in vivo, in saliva. Disintegrationrates in water are measured (in accordance with the EuropeanPharmacopoeia) in an amount of water that is sufficiently large not toreach saturation level in terms of dissolution, whereas in vivo, byvirtue of the small volume of saliva, the excipients are at saturationlevel. Furthermore, the stirring to which the tablets are subjected inthe customary test does not reflect disintegration in the mouth. TheApplicant accordingly found, during comparative tests, that certainexcipients which are known as good disintegrants are not suitable forthe preparation of orodispersible forms. Conversely, certain excipientsthat exhibit average disintegration in water may exhibit advantageousproperties in vivo.

The Applicant then found, surprisingly, that the said granules renderedthe tablets highly suitable for disintegration in the mouth, that beingthe case over a wide tablet hardness range, whilst maintaining a lowlevel of friability, which is especially remarkable. Most orodispersibleforms of the prior art which disintegrate rapidly in the mouth arehighly friable, which is reflected by the need to use a specificpackaging and the risk of the tablet disintegrating as soon as it ishandled and taken out of its pack.

It is especially remarkable that the above-mentioned criteria oforodispersibility and low friability are maintained over a wide tablethardness range, that is to say for tablets having a hardness of from 15to 30 Newtons.

The pharmaceutical compositions according to the invention arepreferably characterised in that they comprise, in relation to the totalweight of the tablet:

-   -   from 5% to 20% by weight of ivabradine or a pharmaceutically        acceptable salt thereof, even more preferably from 7.5% to 10%,    -   from 75% to 94% by weight of STARLAC®.

They may optionally comprise from 0.1% to 3% by weight of lubricatingagents such as magnesium stearate or sodium stearyl fumarate, preferablyfrom 0.5% to 1.5%, and from 0.1% to 3% by weight of a flow agent such ascolloidal silica, preferably from 0.5% to 1.5%.

The following Examples illustrate the invention without limiting it inany way:

Orodispersible ivabradine tablets

EXAMPLE 1

Formulation: Finished tablet of 100 mg Constituents Amount (mg)Ivabradine hydrochloride 7.5 Starlac ® 91.5 Magnesium stearate 0.5Anhydrous colloidal silica 0.5

EXAMPLE 2

Formulation: Finished tablet of 100 mg Constituents Amount (mg)Ivabradine hydrochloride 10 Starlac ® 88.5 Sodium stearyl fumarate 1Anhydrous colloidal silica 0.5

The tablets are prepared by mixing the constituents, followed by directcompression. The hardness of the tablets of Examples 1 and 2 is about 20Newtons.

In order to determine the disintegration time in the mouth, theorodispersible ivabradine tablets described in Examples 1 and 2 wereplaced in the mouth. In these. tests it was found that, for each of theformulations tested, the disintegration time in the mouth was less than1 minute.

1-10. (canceled)
 11. A solid orodispersible pharmaceutical compositioncomprising: granules consisting of co-dried lactose and starch, andivabradine or a pharmaceutically acceptable salt thereof.
 12. Acomposition according to claim 11 wherein the composition disintegratesin the mouth in less than three minutes.
 13. A composition according toclaim 12 wherein the composition disintegrates in the mouth in less thanone minute.
 14. A composition according to claim 11, comprising, inrelation to the total weight of the composition: from 75% to 94% byweight of granules consisting of co-dried lactose and starch, and from5% to 20% by weight of ivabradine or a pharmaceutically acceptable saltthereof.
 15. A composition according to claim 14, comprising from 7.5%to 10% by weight of ivabradine or a pharmaceutically acceptable saltthereof.
 16. A composition according to claim 11, further comprising oneor more lubricants and a flow agent.
 17. A composition according toclaim 11, wherein the composition is in the form of a tablet.
 18. Atablet according to claim 17, wherein the tablet is obtained by directcompression.
 19. A tablet according to claim 18, wherein the tablet hasa hardness from 15 to 50 Newtons.
 20. A tablet according to claim 19,wherein the tablet has a hardness of about 20 Newtons.
 21. A process forthe manufacture of solid orodispersible compositions of ivabradine, or apharmaceutically acceptable salt thereof, which disintegrate in themouth in less than three minutes, wherein the ivabradine, or apharmaceutically acceptable salt thereof, is mixed with granulesconsisting of co-dried lactose and starch.
 22. A process for themanufacture of solid orodispersible compositions of ivabradine, or apharmaceutically acceptable salt thereof, which disintegrate in themouth in less than one minute, wherein the ivabradine, or apharmaceutically acceptable salt thereof, is mixed with granulesconsisting of co-dried lactose and starch.
 23. A method for treating aliving animal body, including a human, afflicted with a conditionselected from stable angina, heart failure and acute ischaemiacomprising the step of administering to the living animal body,including a human, a composition according to claim 11 which iseffective for alleviation of the condition.